PROJECT SUMMARY/ABSTRACT This Atopic Dermatitis Research Network-Clinical Research Center (ADRN-CRC) proposal aims to establish a clinical and laboratory infrastructure to support the ADRN-Leadership Center (ADRN-LC). The current proposal will evaluate the endotypes underlying three AD phenotypes: AD patients with propensity to eczema herpeticum (ADEH+), AD without a history of eczema herpeticum (ADEH-) and AD with food allergy (AD+FA+). We propose that these different phenotypes and endotypes of AD are associated with different skin barrier profiles that can be defined by genomics, lipidomics, transcriptome, and proteomics. The project will establish a clinical and administrative infrastructure of trained clinical staff with capabilities of recruiting adult and pediatric AD populations, clinical research facilities, investigational pharmacy services, IRB personnel, and laboratory facility capable of conducting single-center ADRN-CRC and multi-center clinical research for the ADRN Consortium in the areas of mechanisms and treatment of AD. Here, we propose two CRC-specific research projects as outlined in this application. Project 1 will focus on mechanisms of disseminated viral infections in eczema herpeticum. The project will utilize archived and newly established keratinocyte and fibroblast cell lines from skin biopsies of ADEH+ and ADEH- subjects and non-atopic controls. We intend to evaluate the role of nine novel ADEH+ genetic risk mutations identified by the study group in anti-HSV-1 responses and keratinocyte differentiation. In addition, the contribution of sphingolipid metabolism and S1P in HSV replication will be examined. Lastly, epidermal differentiation program of ADEH+ keratinocytes influenced by prior in vivo exposures to the cytokine environment and viral exposure will be evaluated. Project 2 will assess skin barrier abnormalities and oxidative stress response in the skin of AD patients with FA. The project will characterize skin barrier function of AD+FA+ children and adults through clinical and skin tape strip lipidomic and proteomic assessment. Evidence for oxidative stress responses in AD+FA+ skin samples and its link to skin barrier abnormalities in these subjects will be examined through the analysis of expression of oxidative stress response enzymes, oxidative protein modifications in skin tape strip samples, and responses to oxidants of the organotypic skin cultures from AD+FA+ subjects. The projects will provide new knowledge about AD endotypes, biomarkers for disease assessment, and novel molecular targets for clinical disease interventions.